Lysosomal storage disorders (LSDs) encompass a group of more than 40 diseases resulting from a variety of enzyme deficiencies. LSDs usually present at an early age and can result in debilitating phenotypes. LSD patients commonly have an accumulation of specific macromolecules within tissues and cells, leading to clinical features including liver and spleen enlargement, neurologic findings such as mental retardation, skeletal dysplasia, opthalomological abnormalities and hematological effects such as granulation and vaculoation of lymphocytes. Subgroupings of LSDs based on the nature of the macromolecule that accumulates include mucopolysaccharidoses (MPS), gangliosidoses, glycosphingolipidoses, glycoproteinoses, mucolipidoses, leukodystrophies and disorder of neutral lipids.
MPS account for the largest single subgroup of LSDs. The MPS are inherited disorders, resulting from insufficient levels of specific lysosomal enzyme activity, involved in degradation of glycosaminoglycans (GAGs). Accumulation of these undegraded or partially degraded GAGs interferes with the normal function of cells, tissue and organs and affects the normal growth and development of the individual.
The overall prevalence of MPS is estimated at about 1/20,000 (MEIKLE P J et al. (1999) JAMA. 281:249-54). A myriad of mutations have been identified for each of the MPS disorders, making genetic screening by itself inefficient. Genotype/phenotype correlation does exist for some deficiencies. However, the variety of mutations for each deficiency makes this prediction difficult in a considerable proportion of patients (TERLATO N J and COX G F. (2003) Genet. Med. 5:286-294). Initial diagnostic inquiries are based on clinical phenotype presentation, and this may be used to guide selection of further biochemical assays.
Highly specific substrates and assays for enzyme activity have been developed to assist the diagnostic process, but these often require invasive tissue sampling and may be time consuming as cells are cultured to provide sufficient quantity for screening. Furthermore, traditional enzyme assays are generally MPS type specific and are thus not amenable to use for general MPS screening. Also, in very young children specific diagnosis may not be possible until the disease has advanced sufficiently to result in damage that may be irreversible. Even if a definitive diagnosis is made and an effective therapy is initiated as early as possible, the disease may have progressed sufficiently to result in irreversible damage.
Assays for urinary GAGs are known and have been used extensively for screening, diagnosing and monitoring MPS patients. However the levels of urinary GAGs may not correlate with disease severity (BYERS S et al. (1998) Mol. Genet. Metab. 65:282-290; GALLEGOS-ARREOLA M P et al. (2000) Arch. Med Res. 31:505-510; MABE P et al. (2004) Clin. Chim. Acta 345:135-140; MAHALINGAM, K. et al. (2004) Indian J Pediatr. 71:29-32).
Lysosomal proteins have been found at elevated levels in the lysosomes from affected individuals, and are reported as general LSD markers (HUA C T et al. (1998) Clin Chem. 44(10):2094-2102; MEIKLE P J et al. (1997) Clin Chem. 43(8):1325-35).
Additional markers of LSD and MPS would be useful. Particularly, markers that correlate with disease severity.